The insulin-like growth factor-I receptor (IGF-IR) is a tyrosine kinase membrane receptor having a structure very similar to that of the insulin receptor (IR). The structure of IGF-IR consists of two extracellular α-chains that form the ligand-binding domain and two β-chains that make up the transmembrane and intracellular domains. IGF-IR is the primary receptor for insulin-like growth factor IGF-I, although IGF-II and insulin can also bind with less affinity. Upon ligand binding, IGF-IR is activated, resulting in autophosphorylation of tyrosines on the intracellular β-subunit. IGF-IR then phosphorylates intracellular proteins such as the insulin receptor substrates 1 to 4 (IRS1-IRS4) and Shc. These substrates, in turn, initiate phosphorylation cascades that activate the phosphatidylinositol 3-kinase (PI-3K)/protein kinase B (Akt) or mitogen-activated protein kinase (MAPK) pathways (Samani et al. Endocr. Rev. 28:20-47 (2007)).
Through activation of these signaling cascades, IGF-IR has been implicated in cancer. The exact role of IGF-IR in cancer, however, remains uncertain and appears to vary according to tumor or cell type. For example, some tumors may depend on IGF-IR signaling for survival, whereas others rely on IGF-IR for proliferation. Yet other tumors may employ IGF-IR overexpression as a mechanism of resistance against cytotoxic agents such as anti-cancer drugs (Rodon et al. Mol. Cancer Ther. 7:2575-2588 (2008)). Accordingly, inhibition of IGF-IR is an attractive drug strategy for cancer treatment.
Although IGF-IR was first cloned in the 1980s, drug development to target IGF-IR has been slow to develop. Currently, there are close to 30 drug candidates that target IGF-IR in various clinical phases including both monoclonal antibodies and small molecule tyrosine kinase inhibitors, but no molecule has yet received FDA approval for cancer treatment (Rodon et al. Mol. Cancer Ther. 7:2575-2588 (2008); Gualberto et al. Oncogene 28:3009-3021 (2009)). There remains a clear need to target IGF-IR through the development of potent inhibitors of this receptor.